Project Summary Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are common outcomes following trauma that are frequently comorbid, and this comorbidity is associated with greater symptom severity and poorer prognosis. Thus, efforts to better understand the etiology of these conditions is important for decreasing negative outcomes and improving prevention and treatment efforts, as much is still unknown regarding the etiology and mechanisms involved in their co-occurrence. Recent research has found that in addition to both phenotypes being moderately heritable, there is a modest degree of overlap in their latent genetic risk. Moreover, there is reason to suggest that fear-learning mechanisms frequently associated with PTSD may also be associated with AUD. Areas in need of further research include identification of molecular variation responsible for AUD/PTSD comorbidity, and extension of fear-learning models to AUD and comorbid AUD/PTSD populations. Developments in statistical procedures have afforded the ability to leverage genome- wide association data to answer key questions about these shared molecular underpinnings. The overarching goals of this K01 proposal are threefold. First, the study aims to use existing large-scale genome-wide data from the Psychiatric Genomics Consortium (PGC; PTSD and Substance Use Disorders workgroups) to examine the molecular overlap via bivariate single nucleotide polymorphism (SNP)-based heritability models, and determine if the polygenic risk score (PRS) from each disorder predicts case status in the other dataset. Second, a clinical laboratory study will be conducted using fear-conditioning paradigms in a trauma-exposed sample of diagnosis free controls, AUD, PTSD, and comorbid AUD/PTSD diagnostic groups to determine if deficits in learning are shared. Finally, an exploratory aim will use the PRS scores from the PGC data to generate risk scores in the lab sample to examine if there is a genetic association with conditioning deficits. To achieve these aims, the candidate and multidisciplinary mentorship team have developed a comprehensive training plan that delineates a series of training and research goals. These goals will incorporate training in the epidemiology and genetics of AUD and PTSD, molecular and statistical genetics techniques, and conduct of clinical laboratory paradigms using genetic and psychophysiological measures. This training and resultant findings will capitalize on existing expertise and provide additional, focused training to allow for the development of a multimodal research program that uses large-scale genetic association findings to develop mechanism-focused laboratory studies that inform upon the development and maintenance of this complex presentation. The proposed research represents an important contribution towards advancing our understanding of the complicated and frequently comorbid phenotypes of AUD and PTSD. The institutional environment is ideal for the candidate's goal of developing an independent research line that ultimately aims to decrease the burden of alcohol-related problems, consistent with NIAAA research priority.